The U.S. Food and Drug Administration today approved the anti-clotting drug Eliquis (apixaban), an oral tablet used to reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem.

Atrial fibrillation, one of the most common types of abnormal heart rhythm, is an abnormal, irregular, and rapid beating of the heart in which the heart’s two upper chambers (atria) do not contract properly, allowing blood clots to form in them. These clots can break off and travel to the brain or other parts of the body.

“Blood clots in the heart can cause a disabling stroke if the clots travel to the brain,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “Anti-clotting drugs lower the risk of having a stroke by helping to prevent blood clots from forming.”

The safety and efficacy of Eliquis in treating patients with atrial fibrillation not caused by cardiac valve disease were studied in a clinical trial of more than 18,000 patients that compared Eliquis with the anti-clotting drug warfarin. In the trial, patients taking Eliquis had fewer strokes than those who took warfarin.

Patients with prosthetic heart valves should not take Eliquis nor should patients with atrial fibrillation that is caused by a heart valve problem. These patients were not studied in clinical trial. As with other FDA-approved anti-clotting drugs, bleeding, including life-threatening and fatal bleeding, is the most serious risk with Eliquis. There is no agent that can reverse the anti-coagulant effect of Eliquis.

Eliquis will be dispensed with a patient Medication Guide that provides instructions on its use and drug safety information. Health care professionals should counsel patients on signs and symptoms of possible bleeding.

Eliquis is manufactured Bristol-Myers Squibb Company of Princeton, N.J. and marketed by BMS and Pfizer Inc. of New York.

The Common Fund's Human Microbiome Project (HMP) aims to characterize the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease. HMP includes the following initiatives.

The PCORI Challenge Initiative: Connecting Ideas for Research Collaboration

At PCORI, our mandate is to support research that will help patients and those who care for them make better-informed health and health care decisions. To meet this goal, we’ve made it clear that we plan to support “research done differently,” requiring, among other things, that the projects funded provide mechanisms for meaningful involvement of patients and caregivers throughout the research process.
But how might researchers who are committed to engaging in such collaborative work connect with potential patient or caregiver partners? And how might patients or caregivers interested in working with researchers, or who have research ideas they’d like to see turned into a rigorous scientific study, connect with the investigators who can help to make that a reality?
We think these questions add up to an excellent opportunity for PCORI’s first “challenge” initiative – using an “open innovation” approach to problem-solving to tap into the expertise of our patient and other stakeholder communities. The solution we are asking for is creation of a “matching system” to link patients and scientists as partners in conducting research. It could be a well-articulated conceptual model, adaptation of an existing matching protocol reimagined for the purpose outlined in this challenge, a prototype for an entirely new web-based service or app, some combination of these approaches, or something else entirely.This challenge, which we’re launching in collaboration with Health 2.0, offers an opportunity for innovators to help PCORI pursue our commitment to “research done differently” by bringing the voice of patients, caregivers and other stakeholders clearly and fully to the research process. We believe this means having patients and caregivers serve as collaborators with researchers in such critical activities as formulating research questions, developing research materials, determining research protocols, and helping to review and disseminate study results.PCORI requires this focus on engagement in our funding announcements, which leverage the broad research community’s expertise in proposing topics for study but stipulate that patients and other stakeholders be meaningful members of research teams. We believe that if the research we fund is to have impact on patient outcomes, it is essential to promote involvement by and consensus among key patients and stakeholders from the start in identifying the questions to be studied and agreeing they are important. Patients and other stakeholders need to feel a sense of ownership of the research process, and embracing research is easier when its origins are transparent, traceable and reflective of your needs.
We know that what we propose in this regard is neither traditional nor simple. Although the research community has extensive experience in recruiting patients as study subjects, engaging them as meaningful “collaborators” in research is not routine. We know many researchers are interested in taking this approach but don’t necessarily know the best or most effective way to proceed. Likewise, we know many patients and caregivers are interested in working with researchers, or might have research questions they would like to see tested in a rigorous study, but are unsure of how to make the connection that will allow them to see that done. Thus, we’d like to create a matchmaking system to bring them together.
A panel of reviewers, including researchers, technologists, patients and other stakeholders, will assess the entries. The review panel will judge entries, whether conceptual models or prototypes, based on how well they address the following criteria:

The entry’s actual or described technical capacity to efficiently and effectively connect patients and researchers, across multiple platforms and levels of complexity.

Usability, scalability and sustainability across diverse populations with differing levels of access to, understanding of and experience with technology and health/health care information.

Differences in the ways that patients, caregivers and researchers understand, describe and seek answers to the problems they face or the issues they’re trying to address (e.g., different terms for similar concepts, general levels of health literacy, etc.).

Maximizing “patient-centeredness” – the submission’s ability to account for and effectively focus on and address patients’ needs – while also emphasizing and facilitating researchers’ need to emphasize the scientific rigor of any resulting collaboration.

The particular challenges of serving “hard-to-reach” audiences, including, but not limited to, ethnic and racial minorities, rural populations, the elderly, the disabled/physically challenged and those for whom English is not their native language.

Winners will receive cash prizes and their work may be considered for additional PCORI support, depending on the outcome of the review process.
We think this will be a compelling challenge that will resonate with researchers, patients, the caregiver and advocacy communities, developers and entrepreneurs, and anyone else with a creative mind and interest in improving health and health care. Whichever of these groups describes you, we hope you’ll take up this challenge. We very much look forward to seeing what you come up with.Anne Beal, MD, MPH, is PCORI’s Deputy Executive Director and Chief Operations OfficerSue Sheridan, MBA, MIM is PCORI’s Director of Patient Engagement

Abstract

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

Source

Abstract

BACKGROUND:

Homozygosity for UGT1A1*28/*28 (Gilbert's variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals.

METHODS:

We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually.

Source

Abstract

PURPOSE:

Recent studies have identified genetic variants associated with both increased serum PSA concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on PSA levels, it may be possible to create a personalized PSA cutoff to more accurately identify individuals for whom biopsy is recommended. We therefore determined how many men would continue to meet common biopsy criteria after genetic correction of their measured PSA concentrations.

MATERIALS AND METHODS:

The genotypes of 4 single nucleotide polymorphisms (SNPs) previously associated with serum PSA levels (rs2736098, rs10788160, rs11067228, and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of the PSA was performed by dividing an individual's PSA value by his combined genetic risk. Analyses were used to compare the percentage of men that would meet commonly used biopsy thresholds (≥2.5 or ≥4.0 ng/mL) before and after genetic correction.

RESULTS:

Genetic correction of serum PSA results was associated with a significantly decreased frequency of men meeting biopsy thresholds. Genetic correction could lead to a 15% and 20% relative reduction in the total number of biopsies using a biopsy threshold of ≥2.5 or ≥4.0 ng/mL, respectively. In addition, genetic correction could result in an 18-22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses.

Abstract

Ten years after the Human Genome Project, medicine is still waiting for many of the promised benefits, and experts have tempered their high expectations. Public opinion on genetic testing has generally been favourable but is this still the case? The aim of this study is to compare public experiences, beliefs and expectations concerning genetic testing over the years (2002 vs 2010). A cross-sectional questionnaire survey was conducted using the Dutch Health Care Consumer Panel in 2002 and 2010. Responses to questions in identical wording were compared. In 2002 and 2010, 817 (63%) and 978 (70%) members responded, respectively. Awareness and reported use of genetic tests remained stable over time. In 2010, more respondents expected genetic testing to become more widely applied, believed that knowledge about the genetic background of disease helps people live longer, and that testing should be promoted more intensively. In 2010, they were also more interested in their own genetic make-up. On the one hand, the concern that a dichotomy would emerge between people with 'good genes' and 'bad genes' was higher. On the other hand, respondents thought that insurance companies would be less likely to demand a genetic test in order to calculate health insurance premiums. In conclusion, the results suggest that in 8 years, expectations of benefits and potential use of genetic testing have been raised among the public, resulting in more positive opinions. Worries on inequity remain, although worries about premium differentiation by insurance companies have decreased.European Journal of Human Genetics advance online publication, 19 December 2012; doi:10.1038/ejhg.2012.271.

Getting My Whole Genome Sequence

Eric Topol, MD, Genomic Medicine, 10:24PM Dec 14, 2012

Eric Topol, MD: Director, Scripps Translational Science Inst.

In this segment, I describe the experience of seeing the 3.3 million variants in my genome compared with the 3 billion bases in the reference human genome on my iPad via the 99-cent "My Genome" app. This comes after participating on the faculty at Illumina's inaugural "Understanding My Genome" conference and is of particular interest considering a review paper we just published on the role of pharmacogenomics in clinical practice.
Reference
Harper AR, Topol EJ. Pharmacogenomics in clinical practice and drug development. Nat Biotechnol. 2012;30:1117-1124.

1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Idiopathic dilated cardiomyopathy (IDC) is defined by the presence of left ventricular dilatation and systolic dysfunction in the absence of an underlying cause, such as hypertension, valve disease or coronary artery disease, sufficient to cause global systolic impairment.

It’s All About the Genes and the Brain Machines

Gene medicine: Increasingly, genomic information is being used in the practice of medicine. Meanwhile, attempts at using gene therapy to treat rare genetic diseases is enjoying a resurgence. The amount of time and money needed to sequence genomes continued to fall this year, perhaps to no one’s surprise. But while the field seemed to be finally approaching the heralded $1,000 human genome, the implications of reaching that milestone are not clear. Without expert analysis, the result of sequencing a human genome is just a large file of letters. You still need to manipulate and understand what those letters mean. Different companies announced services to help, from initial processing and storage of data to interpretation of the genetic data into medical meaning.
As human genomics garnered more attention from the medical community, the technology attracted new business opportunities. In April, the company behind the most widely used DNA sequencer, Illumina, fought off a hostile bid from pharmaceutical giant Roche. Just seven months later, Illumina tried to take over Complete Genomics, a company with technology well suited to medical genomics but which has never achieved financial success. That offer followed what seemed to be an all-but-assured purchased of Complete Genomics by China’s BGI. Illumina and BGI continue to fight over Complete Genomics.

Still, the medical community is only at the cusp of its understanding of how genome sequences can be used to help patients. Two branches of medicine that seem to be at the forefront of bringing on board DNA technology are reproductive medicine and cancer. Early in the summer, scientists at the University of Washington in Seattle reported a technique for determining the genome sequence of a fetus by analyzing DNA in the mother’s blood and from the father. Illumina’s CEO Jay Flatley said that prenatal diagnostics will be a major focus for the company, which has been expanding its business from sequencer manufacturing to broad DNA analysis service. In September, Illumina purchased BlueGnome, a chromosome-focused diagnostic company whose technology can detect abnormal numbers of chromosomes in IVF embryos. DNA analysis could also help prior to conception, according to a start-up called GenePeeks. That company announced it would offer predictive genome analysis for sperm bank clients to help guide them away from risky donor matches.
Cancer patients and their doctors were also early adopters of medical genome science this year. Cancer is a disease of the genome: genetic mutations lead to abnormal cellular proliferation and behavior. Each person’s tumor and even different cells within a single tumor can have a unique profile of mutations, which makes finding the right drug to treat each patient difficult. Cambridge, Massachusetts-based Foundation Medicine offered a sequencing service that searches for mutations that can be addressed with drugs in a patient’s tumor. Another Cambridge company, H3 Biomedicine, is using public databases of tumor sequences to find new drug targets specific to certain patient populations.
Genetic medicines also got a boost with the first Western approval of gene therapy in November. Amsterdam-based Uniqure will begin selling its virus-mediated gene correction for a rare metabolic disorder sometime next year. The announcement could be good news for other companies trying to develop gene therapies as well as other groups developing molecular medicines, such as gene-silencing RNAi treatments that continue to move through clinical trials.
Although still untested in patients, another genetic manipulation is proving to be a powerful tool for neuroscientists. With optogenetics, scientists can manipulate neuron activity with flashes of light, and this year a group demonstrated for the first time that primate behavior could be controlled with the technique. Lab animal studies this year suggest optogenetics might one day help patients with blindness caused by retinal degeneration.
The melding of mind and machine was also big this year. Scientists in Winston-Salem, North Carolina, demonstrated that a brain implant could replace some cognitive function in primates, which could one day help people with brain damage. On the flip side, two research groups published the first accounts of quadriplegic people using brain implants to control robotic limbs. The implants recorded the participants’ intentions to move, which were translated by a computer into instructions for a robotic arm. The idea is that one day people with severe paralysis or amputations could use such neural prosthetics at home to help with the tasks of daily life.
Brain electronics were also implanted into Alzheimer’s patients this year in an attempt to slow a disease that has so far evaded pharmaceutical treatment. The urgency for treatment is growing, but the community still doesn’t know what sets into motion the cascade of molecular events that robs people of their memory and thinking skills. With better diagnostic tools and the discovery that there are warnings decades before symptoms, scientists are turning to treating patients with a genetic predisposition for the disease before they start having symptoms. Perhaps this will be the key to treatments in future years.

Genomes That Got Sequenced: Class of 2012

In the time when DNA sequencing is cheap, sequencing a genome doesn’t make much noise (except if it is a BigFoot genome). But still, a number of interesting species/genomes got sequenced this year and made it to the public. Even in the era where we can sequence everything for cheap, the sequenced whole genomes are of a great resource and help us improve our understanding genome evolution. In addition to the sequences, these genomes also gave us interesting Venn diagrams and pig walkingplots.

Got Sequenced?

Here is the (incomplete) list of species that “Got Sequenced” and made it to the big league in the year 2012. The sequenced species/range from tiny leech to extinct Denisovan.

ELECTROPHORESIS

This paper represents the collective work of the Ion Torrent R&D Team over the past three years. This is a team of over 300 people, in which many people have made important contributions. For a full list of members of this team, please see the Addendum at the end of this manuscript.

Keywords:

Biosensor;

CMOS sensor array;

DNA sequencing;

ISFET;

Next-generation sequencing

Abstract

In order for next-generation sequencing to become widely used as a diagnostic in the healthcare industry, sequencing instrumentation will need to be mass produced with a high degree of quality and economy. One way to achieve this is to recast DNA sequencing in a format that fully leverages the manufacturing base created for computer chips, complementary metal-oxide semiconductor chip fabrication, which is the current pinnacle of large scale, high quality, low-cost manufacturing of high technology. To achieve this, ideally the entire sensory apparatus of the sequencer would be embodied in a standard semiconductor chip, manufactured in the same fab facilities used for logic and memory chips. Recently, such a sequencing chip, and the associated sequencing platform, has been developed and commercialized by Ion Torrent, a division of Life Technologies, Inc. Here we provide an overview of this semiconductor chip based sequencing technology, and summarize the progress made since its commercial introduction. We described in detail the progress in chip scaling, sequencing throughput, read length, and accuracy. We also summarize the enhancements in the associated platform, including sample preparation, data processing, and engagement of the broader development community through open source and crowdsourcing initiatives.

Abstract (provisional)

Synthetic genetic arrays (SGA) have been very effective at measuring genetic interactions in yeast in a high throughput manner and recently have been expanded to measure quantitative changes in interaction, termed 'differential interactions', across multiple conditions. Here, we present a strategy that leverages statistical information from the experimental design to produce a novel, quantitative differential interaction score, which performs favorably compared to previous differential scores. We also discuss the added utility of differential genetic-similarity in differential network analysis. Our approach is preferred for differential network analysis, and our implementation, written in MATLAB, can be found at http://chianti.ucsd.edu/~gbean/compute_differential_scores.m.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Source

Abstract

OBJECTIVE:

To conduct a nationwide survey of the methods used in newborn screening (NBS) programs to notify birthing centers, pediatricians, and parents of the results of NBS tests in every state and territory.

STUDY DESIGN:

State and territory NBS program representatives were identified and contacted via e-mail. Each state or territory responded to a survey asking questions about their methods (eg, telephone, e-mail, surface mail) for reporting normal, borderline, and abnormal results.

RESULTS:

With 100% of states and territories responding, a broad array of reporting methods were identified with substantial variability between states for delivering NBS test results to the responsible entities. Mail, telephone, and facsimile were the predominant reporting methods. The majority of states and territories did not have Web-based reporting methods.

Source

Abstract

PURPOSE:

Severe combined immunodeficiency (SCID) is characterized by failure of T lymphocyte development and absent or very low T cell receptor excision circles (TRECs), DNA byproducts of T cell maturation. Newborn screening for TRECs to identify SCID is now performed in several states using PCR of DNA from universally collected dried blood spots (DBS). In addition to infants with typical SCID, TREC screening identifies infants with T lymphocytopenia who appear healthy and in whom a SCID diagnosis cannot be confirmed. Deep sequencing was employed to find causes of T lymphocytopenia in such infants.

METHODS:

Whole exome sequencing and analysis were performed in infants and their parents. Upon finding deleterious mutations in the ataxia telangiectasia mutated (ATM) gene, we confirmed the diagnosis of ataxia telangiectasia (AT) in two infants and then tested archival newborn DBS of additional AT patients for TREC copy number.

RESULTS:

Exome sequencing and analysis led to 2 unsuspected gene diagnoses of AT. Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California's newborn screening program. AT children with low neonatal TRECs had low CD4 T cell counts subsequently detected (R = 0.64).

CONCLUSIONS:

T lymphocytopenia in newborns can be a feature of AT, as revealed by TREC screening and exome sequencing. Although there is no current cure for the progressive neurological impairment of AT, early detection permits avoidance of infectious complications, while providing information for families regarding reproductive recurrence risks and increased cancer risks in patients and carriers.

Newborn screening for fragile X syndrome (FXS) is feasible, but a higher-than-expected prevalence of premutation and "gray zone" alleles may complicate analysis of the public health burden of testing, according to results from a study by Flora Tassone, PhD, from the University of California, Davis, and colleagues, published online December 21 in Genome Medicine. A Spectrum of Mutations and Manifestations
FXS is the most common cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). It is caused by extra CGG repeats in the first exon of the fragile X mental retardation 1 ( FMR1) gene, which encodes part of the 5' untranslated region of the corresponding mRNA.
Most people have 29 or 30 CGG repeats in the gene. In individuals with the full mutation, exceeding 200 repeats, extended methylation turns off the gene, which adversely affects synaptic plasticity. Affected children have ID, behavior problems, social deficits, and ASD.
Individuals with the premutation have between 55 and 200 copies of the CGG repeat. Because the extended allele is unstable and can grow with generations, premutation carriers are at increased risk of having children with FXS. Premutation carriers are also at elevated risk of developing childhood- or adult-onset neurological disorders, including ASD, attention-deficit/hyperactivity disorder, anxiety, and depression.
Women with the premutation face a 20% risk of developing fragile X–associated primary ovarian insufficiency, and 40% of older male and between 8% and 16% of older female premutation carriers develop fragile X–associated tremor ataxia syndrome. Others may develop milder neurological problems, such as neuropathy or balance disorders.
Individuals who have 40 to 54 repeats are in the "gray zone," which is not well understood but may increase risk for fragile X–associated tremor ataxia syndrome and fragile X–associated primary ovarian insufficiency, and "can be unstable when transmitted across generations," the authors explain. .
The prevalence in the general population of the full mutation is between 1:2500 and 1:8000 for females and 1:400 and 1:5000 for males, and the prevalence of the premutation is between 1:130 and 1:256 for females and 1:250 to 1:813 for males. Prevalence varies in different populations. FXS Testing As Part of Newborn Screening
Although newborn screening recommendations in 2006 from the American College of Medical Genetics did not include FXS, encouraging results in early-phase clinical trials in toddlers as well as an improved polymerase chain reaction–based method to detect repeats suggest that newborn diagnosis may one day be actionable.
The authors report results of a pilot newborn screening study to assess the prevalence of different CGG repeat sizes in FMR1. They analyzed 14,207 blood spots from newborns (7312 boys and 6895 girls) collected from November 2008 through May 2012 from the University of California Davis Medical Center; Rush University Medical Center in Chicago, Illinois; and the University of North Carolina Hospital in Chapel Hill. Parents of newborns found to have the premutation were offered a follow-up medical visit, confirmatory blood testing, and genetic counseling.
The study detected a single full-blown case; the sample was not large enough to find more. Prevalence of the premutation was 1:209 girls (95% confidence interval, 1:303 - 1:149) and 1:430 (95% CI, 1:736 - 1:268) in boys. The study found 33 girls and 17 boys with the premutation, with a mean CGG repeat number of 70, ranging from 55 to 130.
Prevalence for gray zone expansions was 1:66 for girls (95% CI, 1:80 - 1:54) and 1:112 for boys (95% CI, 1:145 - 1:88). The study found gray zone expansions in 105 girls and 65 boys, with a mean CGG repeat number of 48, ranging from 45 to 54. Whites had more gray zone expansions than Hispanics and blacks, but not significantly more.
The researchers conclude that implementation of newborn screening for fragile X mutations requires better understanding of the effects of intermediate repeat numbers and analysis of the effect of informing families about these uncertain findings. Prevalence Results "Not Surprising," but Study Raises Ethical Dilemma
"It's not surprising that the study found a higher prevalence of the premutation than has been previously reported, because the screening method allowed more precise quantification of the alleles using a next-generation [polymerase chain reaction] patented by Asuragen," Dejan Budimirovic, MD, director of the Fragile X Clinic at the Kennedy Krieger Institute in Baltimore, Maryland, told Medscape Medical News. He agrees with the researchers' call for more studies of clinical outcomes associated with the premutation. Dr. Budimirovic was not involved in the study.
Michael Tranfaglia, MD, medical director of the FRAXA Research Foundation, who was also not involved in the study, cites the uncertainties associated with the premutation and gray zone state as challenges to newborn screening. "A premutation confers risk of some things, but nothing certain, as is the case with the full mutation, which causes developmental disorders in all males. This information could be useful for family planning and other major decisions later in life, but exactly how to best present this information is unclear," he told Medscape Medical News. Gray zone alleles, he adds, present an ethical quandary, because associated risks are unclear. "It's uncertain whether 'gray zone status' should be reported to families, given our current understanding." The study was supported by the National Center for Advancing Translational Sciences, the Eunice Kennedy Shriver National Institute for Child Health and Human Development, and the Centers for Disease Control in conjunction with the Association for Prevention Teaching and Research. One author has led treatment trials for autism and FXS and/or consulted for Roche, Novartis, Seaside Therapeutics, Forest, and Curemark. The remaining authors, as well as Dr. Budimirovic and Dr. Tranfaglia have disclosed no relevant financial relationships. Genome Med. Published online December 21, 2012. Full text

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States.

Abstract

ABSTRACT:

BACKGROUND: Population screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US.

METHODS:

Blood spot screening of 14,207 newborns (7312 males and 6895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach.

RESULTS:

The prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats).

CONCLUSIONS:

The presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported.

Abstract

ABSTRACT:

BACKGROUND: The ability to conduct genome-wide association studies (GWAS) has enabled new exploration of how genetic variations contribute to health and disease etiology. However, historically GWAS have been limited by inadequate sample size due to associated costs for genotyping and phenotyping of study subjects. This has prompted several academic medical centers to form "biobanks" where biospecimens linked to personal health information, typically in electronic health records (EHRs), are collected and stored on a large number of subjects. This provides tremendous opportunities to discover novel genotype-phenotype associations and foster hypotheses generation.

RESULTS:

In this work, we study how emerging Semantic Web technologies can be applied in conjunction with clinical and genotype data stored at the Mayo Clinic Biobank to mine the phenotype data for genetic associations. In particular, we demonstrate the role of using Resource Description Framework (RDF) for representing EHR diagnoses and procedure data, and enable federated querying via standardized Web protocols to identify subjects genotyped for Type 2 Diabetes and Hypothyroidism to discover gene-disease associations. Our study highlights the potential of Web-scale data federation techniques to execute complex queries.

CONCLUSIONS:

This study demonstrates how Semantic Web technologies can be applied in conjunction with clinical data stored in EHRs to accurately identify subjects with specific diseases and phenotypes, and identify genotype-phenotype associations.